Organic compounds and process



2,873,286 ORGANIC COMPOUNDS AND PROCESS J Allan Campbell, KalamazooTownship, Kalamazoo County, John 'C. Bahcock, Portage Township,Kalamazoo County, and John A. Hogg, Kalamazoo Township, KalamazooCounty," Mich., assignors to The Upjohn Company, Kalamazoo, Mich., acorporation of Michigan No Drawing. Application February 14, 1957 SerialNo. 640,090

5 Claims. (Cl. 260-397.45)

The present invention relates to novel steroids and is more particularlyconcerned with 3,B,llfl,l7fi-trihydroxyl7m-methyl-5-androstene, the 3-acylate, the 1113,17/3-diacylate, the triacylate thereof,3/3,17B-dihydroxy-17amethyl-S-androsten-ll-one, theBfi-acylate and the313,175- diacylate thereof.

The novel compounds of the present invention and the process ofproduction thereof may be represented by the following sequence offormulae:

CH3 (1H3 0R OAo ---crn am no A00 CH3 CH3 0: ACC- CH3 CH3 OH 0A0 ---OH3am HO A130 CH CH3 RO- RO IVtl R= IIItl R=H b R=Ao b R=Ao OR i am whereinAc is an acyl radical of an organic carboxylic acid, preferably of ahydrocarbon carboxylic acid containing from one to nine carbon atoms,and R and R are selected from the group consisting of hydrogen and acylradicals of formula Ac, defined as above.

The'process of theinstant invention comprises: treating115,17,3-dihydroxy-17u methyl-4-androsten-3one (I) or an ester thereofwith an acylating agent, for example, an anhydride, a chloride orbromide of an organic carboxylic acid, preferably a hydrocarboncarboxylic acid containing from one to nine carbon atoms or anLisopropenyl acylate wherein the acyl group is of a hydro- United StatesPatent 0 carboxylic acid" esters of 318,11;3,17,B-trihydroxy-l7a-- 2carbon carboxylic acid, at a temperature between sixty degreescentigrade and the reflux temperature of the mixture (at standardpressure) to obtain-the 3,115,175-triacyloxy-l7u-methyl-3,5-androstadiene (II); reducing the thus obtained3,115,17,8-triacy1oxy-l7ix-methyl-3,5- androstadiene (II) with an alkalimetal borohydride such as sodium, potassium, or lithium borohydride toobtain the corresponding3p-hydroxy-ll,B,l7/3-diacyloxyl7a-methyl-5-androstene (Illa);(esterifying compound IIIa produces the corresponding 3fi,l18,l7/8-triacyloxy- 17a methyl 5 androstene (IIIa); (esterifying com-.pound Illa produces the corresponding 33,115,17fitriacyloxy-l7a-methyl-5-androstene (IIIb)); hydrolizing the thusobtained 3 8 hydroxy 11,6,17p diacyloxy methyl 5 androstene or,respectively, the 3,111 8,175 triacyloxy 17a methyl 5 androstene withlithium aluminum hydride to produce 35,115,- 17/8 trihydroxy 17oz methyl5 androstene (IVa); esterifying compound IVa with an acylating agentselected from the halides of organic carboxylic acids, preferably,hydrocarbon carboxylic acids containing from one to nine carbon atoms,inclusive, producing the corresponding 3,8 acyloxy 115,175 dihydroxy 17amethyl 5- androstene (IVb) which can be oxidized with chromic anhydrideto give the corresponding 3fi-acyloxy-l7fi-hy- Hydrolysis of the3fl-acyloxy-l7p-hydroxy-l7a-methyl-5-androsten-- droxy-l7a-methyl-5-androsten-1 l-one (Va).

ll-one with a base such, as sodium hydroxide, potassium hydroxide, orthe like, produces the corresponding3p,17pdihydroxy-17a-methyl-5-androsten-1l-one (Vb). Reesterification ata temperature of sixty degrees up to the reflux temperature of a mixtureof 3fi,l7fl-dihydroxy,l7otmethyl-S-androsten-ll-one with an acidanhydride, defined as above, produces the corresponding di-ester,3,8,l7fl-diacyloxy-17a-methyl-5-androsten-1l-one (Vc).

It is an object of the instant inventionto provide35,11,8,17,8-trihydroxy-17u-methyl-5-androstene, the 3 3- acylate, thellfl,l7,8-diacylate, and the triacylate thereof,3,8,17B-dihydroxy-l7u-methyl-5-androsten-ll-one, the 3,8- acylate andthe 35,175-diacylate thereof. object of the instant invention to theproduction of deficient and anemic patients. They tranquilizing andsedative effect by action on the central be given as m nervous system.The compounds may of hemisuccinates or other esters derived, frompolymethyl-S-androstene or, respectively, 3,3,l7B-dihydroxy-17a-methyl-5-androsten-ll-one. Other monoand ,triesters of318,11p,17/i-trihydroxy-17u-methyl-5-androstene and monoand diesters of3,8,17fl-dihydroxy-17a-methyl- S-androsten-ll-one such as the acetates,propionates, cyclopentylpropionates, dimethylglutarates,v-phenylacetates, or the like, are useful for intramuscular injections.The following examples are illustrative of the process and products ofthe present invention, construed as limiting.

Patented Feb. 10, 1959 group consisting of anhydr'ides and It is anotherprovide a process for r 3,8, l 1 3, 17B-trihydroxy-1h-methyl-S-androstene and 313,17/3-dihydroxy-17a-methyl 5-androsten-.

instant invention,

promote erythropoiesis and are there, fore useful drugs in the treatmentof protein-anabolic but, are not to j EXAMPLE 1 35,] I 5,17 5-trihydrovcy-1 7 z-methyl-S -andrstene 115,1 75-diacetate A-solution was preparedcontaining in 100 milliliters of toluene, five grams of17a-methyl-115-hydroxytestosterone (U. S. 2,735,854) (I) 25 millilitersof acetic anhydride and 100 milligrams of para-toluenesulfonic acid.This solution was heated in a nitrogen atmosphere at reflux fora periodof four and one half hours. Thereafter the solvent was removed in vacuo.The thus obtained residue, crude3,115,175-trihydroxy-17a-methyl-3,5-androstadiene 3,115,175-t1iacetate(II) resisted crystallization. For the subsequent reduction, a solutionof the crude material (II in 100 milliliters of 95 percent ethanol andthree milliliters of ten percent sodium hydroxide solution waspr'epared'and thissolution-w'as cooled to zero degrees,centigrade.- Tothis cooled solution was added a solutionfiof five gr' ams of-sodiumborohydride in. 100 milliliters 'of'seventy-percent aqueous ethanol withstirring and under cooling. After one hour another portion of 2.5 gramsof sodiumborohydride in fifty milliliters of seventy percent aqueousethanol was added. The thus obtained reaction mixture was then stirredfor three days at five degrees centigrade, whereupon fifteen millilitersof ten percent sodium hydroxide solution was added and the solutionheated to near its boiling point. The alcoholwas evaporated invacuoandto the concentrate was added ice and three-normal hydrochloric acidunder stirring Thepre'cipitated product, was collected, washed withwater, dilute hydrochloric acid and water and then dried to yield 4.7grams of 35,115,175-trihydroxy-17amethyl-S-androstene 115,175-diacetate-(111d).

7 ExAMrLE 2 55,1 15,1 7 5-trihydr0xy 1 7a-me'zhy l-5-androstene The35,115,l75-trihydroxy-l7u-methyl 5 androstene 115,175-diacetate ofExample 1 was dissolved in fifty milliliters of tetrahydrofuran andthereto was added 1.5 grams of lithium aluminum hydride with continuousstirring.- After aboutthree minutes the reaction mixture became a hardgeh, Fifty milliliters of ether was then added and the mixture stirredforone hour. Ethyl acetate and waterwere added, the aqueous phase wasseparated and extracted with ether and methylene chloride, and thenon-aqueous phase and, the. extracts werecombined, dried, over anhydrousmagnesium sulfate andfiltered. The filtratevon standing overnightdeposited 1.6 grams of 1 crystals 1 of crude35,115,175-trihydroxy-17a-methyl- S-androstene (IVa). The remainingliquid was concentrated ,to dryness, triturated withgmethylene chlorideto give an additional amount of 1.3 gramsof residue. The two crude cropswere combined and recrystallized from fifteentmilliliters of 3A alcohol(anhydrous ethanol denatured with methanol) containing 0.5 milliliter ofwater to give 1.7 grams of 35,115,175-trihydroxy-17u-methyl-S-androstene which, after another recrystallization from ethyl acetate,yielded 1.2 grams of. pure 35,115,175-trihydroxy-17a-methyl-5-androstene of melting point 230 to 235 degreescentigrade and rotation [061D minus 68 de grees. 1 e

'Analysis.-Calcd. for C H O C, 74.95; H, 10.07. Found: C, 74.53; H,10.16. t e

' The infrared spectrum showed bands for hydroxyl at 3610 and 3280, acarbon-carbon double bond at 1665, and carbon-OH bands at 1146, 1085,1054 and 1030 cm'ri (in Nujol mineral oil).

EXAMPLE 3 ll5-hydroxytestosterone was a hydroxy 17cc 4 hydride in thepresence of toluenesulfonic acid under reflux-conditions togive3,115,l-trihydroxy-17a-methyl-3,5-androstadiene 3,115,175-dipropionate.

Treating the thus obtained3,1l5,175-trihydroxy-17amethyl-3,5-androstadiene 3,115,175-tripropionatewith potassium borohydride in potassium hydroxide solution in aqueousethanol produced 35,1l5,--trihydroxy17amethyl-S-androstene115,175-dipropionate.

EXAMPLE 4 3 5,1 15,1 75-trihydr0xy-17a-methyl-5-ahdrostene115,175-dibutyrate In the same manner givenv in Example 1,flat-methylheated to reflux with butyric anhydride in the presenceofpara-toluenesulfonic acid to give 3,115,175-trihydroxy-17a-methy1-3,5androstadiene 3,115,175-tributyrate. I

Treating the thus obtained 3,115,l75trihydroxy-l7amethyl-3,5-andro'stadiene 3,115,175-tributyratein aqueousalcoholic. solution with sodium b'orohydridea'nd sodium hydroxideproduced 35,115,175-trihydroxy-17m-methyh S-andrcrstene.115,175-dibutyrate. 7

EXAMPLE 5 35,1 15,1 75-tiihydroxy-l 7a-methyZ-5-androstene 1 1 5,175-dibenzoate In the same manner given in Example 1, treating17a-methyl-1l5-hydroxytestosterone with benzoic anhydride in benzenesolution in the presence of paratoluenesulfonic acid produced3,ll5,l75-trihydroxy-17amethyl-3,5-androstadiene 3,115,175-tribenzoate.

Treating the thus produced 3,115,175-trihydroxy-17wmethyl-3,5-androstadiene 3,115,175-tribenzoate in meth anol solutionwith potassium borohydride and aqueous potassium hydroxide solutionproduced 35,115,175-trihydroxy-17a-methyl-5-androstene115,175-tribenzoate.

In the same manner shown in Examples 1, 3, 4, and 5, other35,1l5,175-trihydroxy-17a-methyl 5 androstene 115,175-diacylates areobtained by reacting 17a-methyl- '115-hydroxytestosterone under refluxconditions with an anhydride, a chloride or bromide of an organiccarboxylic acid, preferably a hydrocarbon carboxylic acid'containingfrom one to nine carbon atoms, inclusive, or an isopropenly acylatewherein the acyl group'is of a hydrocarbon carboxylic acid in thepresence of an acid catalyst, such as toluenesultonic acid, sulfuricacid, or gaseous hydrochloric acid, to give the corresponding3,115,175-trimethyl 3,5-androstadiene 3,115,175-triacylate which isthereupon treated with an alkali borohydride, such as sodium, potassium,or lithium borohydride, in aqueous alkali solutions, for example, sodiumhydroxide, potassium hydroxide, or the like, to give the corresponding35,115,175-trihydroxy 17a methyl-S-androstene 115,175-diacylate.Representative diacylates thus prepared include the divalerate,dihexanoate, diheptanoate, dioctanoate, diphenylacetate,di-(trimethylacetate), di-(trifiuoroacetate), and the like diacylates of3 5,1 l 5, l75-trihydroxy-17a-methy1-5-androstene.

EXAMPLE 6 35,11 5,175-trihydr0xy-17a-methyl-5-androstene 3 5,1 15,17,8-triacetate hydroxy-l1ozgmethyl-5-androstene 35,115,175 triacetaterub . EXAMPLE 7 35,115,175-trihydroxy-17a-methyl-5-androstene 35,115,175-tripr0pi0nate In the same manner given in Example 6, reacting 35,115,175 trihydroxy-17u-methyl-5-androstene 115,175-diproprionate withpropionic anhydride in pyridine solution yielded 35,115,175 trihydroxy17u-methyl-5-androstene 35,115,175-tripropionate.

EXAMPLE 8 35,115,] 75 trihydroxy 17u-methyl-5-androstene 35,115,

175-tributyrate In the same manner given in Example 6, 35,115,175,trihydroxy 17a methyl-5-androstene 115,175-dibutyrate was reacted withbutyric anhydride in pyridine solution to give 35,115,175trihydroxy-17a-methyl-5-androstene 35, 1 15,175-tributyrate.

EXAMPLE 9 35,115,] 75 trihyd roxy 17a-methyl-5-androstene 35,115,175-tribenz0ate In the same manner given in Example 6, 35,115,175-trihydroxy 17a-methyl-5-androstene 115,175-dibenzoate was reacted inpyridine solution with benzoyl chloride to give35,115,175-trihydroxy-17a-methyl-5-androstene 35, 1 15, 175-tribenzoate.

EXAMPLE 10 35,115,175 trihydroxy-I 7 oc-methyZ-S -andrstene 35-benzoatel 15,175-aiacetate 115,175-diacylates with acid anhydride or acidchlorides or bromides of organic carboxylic acid or hydrocarboncarboxylic acid produces the corresponding 35,115,175-trihydroxy-l7a-methyl-5-androstene triacylates. In this manner thetrivalerate, trihexanoate, triheptanoate, trioctanoate,triphenylpropionate, or mixed esters like the 35- propionate,115,175-diacetate; the 3-butyrate, 115,175-di- 'benzoate; and similarmixed tri-esters of 35,115,175-trihydroxy-l7a-methyl-5-androstene areobtained.

EXAMPLE 11 35,115,175 trihydroxy-J 7 ot-methyl--androstene 35-aceti ateIn the same manner as given in Example 11, reacting at room temperature,35,115,175-trihydroxy-17e-methyl- S-androstene, dissolved in pyridine,with benzoyl chloride yielded 35,115,175trihydroxy-17a-methyl-5-androstene 35-benzoate.

In the same manner given in Examples 11 and 12, to acting at roomtemperature 35,1l5,175-trihydroxy-17amethyl-S-androstene with acidanhydride or acyl halides of organic carboxylic acids, or, preferablyhydrocarbon carboxylic acids containing from one to nine carbon atoms,inclusive, produces the corresponding 35-acylate of35,115,l75-trihydroxy-17a-methyl-5-androstene. Representative such35-acylates of 35,1l5,175-trihydroxy-17amethyl-S-androstene comprise the35-propionate, butyrate, valerate, isovalerate, hexanoate, heptanoate,octanoate, phenylacetate, phenylpropionate, trifiuoroacetate,hemisuccinate, dimethylbutyrate, or the like.

EXAMPLE 13 35,175 dihydroxy 17a methyl-S-androsten-I]-one 35- acetate Toa solution of 0.5 gram of 35,115,175-trihydroxy- 17a-methyl-5-androstene3-acetate in five milliliters of pyridine was added 0.5 gram of chromicanhydride in five milliliters of pyridine with stirring and cooling.After stirring overnight at room temperature, the mixture was pouredinto water and extracted with methylene chloride. The methylene chloridesolution was washed with water, dried over anhydrous magnesium sulfateand evaporated. The residue was recrystallized from acetone-hexane togive 35,l75-dihydroxy-17wmethyl-5-androsten-1l-one 3- acetate.

EXAMPLE 14 35,175-dihydroxy-17u-methyl-5-androsten-1l-one 35-bcrizoateIn the same manner given in Example 13, 35,115,175-trihydroxy-17a-methyl-5-androstene 35-benzoate was reacted with chromicacid in pyridine solution to give 35,-dihydroxy-17a-methyl-5-androsten-l l-one 35-benzoate.

In the same manner as shown in Examples 13 and 14, oxidizing35,115,175-trihydroxy-17a-methyl-5-androstene 35-monoacylates producesthe corresponding 35,175-dihydroxy-17a-methyl-5-androsten-ll-one35-acy'late, such as for example, the 35-propionate, butyrate, valerate,isovalerate, hexanoate, heptanoate, octanoate, toluate, phenylacetate,phenylpropionate, or the like, of35,175-dihydroxy-l7a-methyl-5-androsten-1l-one.

EXAMPLE 15 35,175-dihydr0xy-1 7oz-methyl-S-altdrosten-l1 -one A solutionof 3 5,l75-dihydroxy-17u-methyl-5-androsten-ll-one 35-acetate inmethanol was freed of oxygen by letting oxygen-free nitrogen pass for aperiod of one hour through the solution. Thereafter under exclusion ofair was added a solution containing fifty milligrams of potassiumhydroxide in two milliliters of methanol freed of oxygen in the mannermentioned before. The thus-obtained mixture was allowed to stand underexclusion of oxygen in a nitrogen atmosphere for a period of eighteenhours, was thereupon poured into 75 milliliters of water, extracted withthree 25-milliliter portions of methylene chloride, the methylenechloride portions combined, washed with water repeatedly, dried overanhydrous sodium sulfate, evaporated and the thus obtained residuerecrystallized from methanol to give35,175-dihydroxy-17emethyl-S-androsten-l l-one.

EXAMPLE 16 35,175 dihydroxy 17oz methyl 5 androsten 11 one35,175-diacetate Exlnvrrrn 17 In the same manner as given in Example 16,35,173- dihydroxy-l7o -methyl--androsten-l l-one was heated with excessof propionic anhydride to give 36,17fi-dihydroxy-17:x-methyl-S-stndrosten-l l-one 35,17fi-dipropionate.

In the same manner given in Examples 16 and 17, other 35,17I3-diacylatesof 3,8,17 5-dihydr0xy-17 a-methyl-S-androsten-ll-one can be prepared byheating 35,17B-dihydroxy 17o: methyl-S-androsten-l l-one with organiccarboxylic anhydrides or, preferably hydrocarbon carboxylic anhydridesto temperatures the refluxing temperature ofthe reaction mixture, andrecovering the: thus produced. 3,8,17fidihydroxy-170trnethyl-i-anrlrosten-l l-one 3fl,t7ii-diacylates. Representative diacylates thus produced comprise thedibntyratc. divalerate,di-isovalerate, dihexanoate, diheptanoate, dioctanoate, diben zoate,diphenylacetate, and the like 0535,-l7fl-dihydroxy-17oc=mcthyl-5-androsten-llrone.

It is to be understood that the inventionis-not to. be limited to theexact details of operation or exact com pounds shown and described, asobvious modifications and equivalents. will be apparent to one skilledin the art, and the invention is therefore to be limited only by thescope of the appended claims.

between sixty degrees and We claim:

1. A compound selected from the group consisting of35,116,17fi-trihyd'roxy 17oz methyl-5: i androsten, 11,3,17B trihydroxya methyl 5 androstene 35- acylates,3fi,11fi,17fi trihydroxy 17a methyl-5..-. androstene 11,8,175 diacylates, 313,116,175 .-trihydroxy-flw,methyl 5 androstene 3 3,115,175 -,triacylates, 3B,17B-dihydroxy 17ozmethyl 5 dihydroxy 17 cc methyl 5 androsten-l l-one 3 8-acylate, 36,17 3dihydroxy 17o: methyl 5 androsten ll-one 3 (1,1713 diacylate, whereinthe acyl radical is of a hydrocarbon carboxylic acid containing from oneto ninecarbon atoms, inclusive.

2. 35,113,173 trihydroxy-17a-methyl-5-androstene. 3. 313,115,175trihydroxy-17 o=-methy1-'5'-androstene: 3B- aceta-te. 4.3n,17,8-dihydroxy-17a-methyl-5-andr0sten-1 1'-one;

5. 3 9,17p-dihydroxy-17m-methyl-5 androsten-11-one 3 8-;

acetate.

References Cited in the file of this patent UNITED STATES PATENTS

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF3B,11B,17B-TRIHYDROXY - 17A - METHYL - 5 - ANDROSTEN, 3B,11B,17B-TRIHYDROXY - 17A - METHYL - 5 - ANDROSTENE 3BACYLATES, 3B,11B,17B -TRIHYDROXY - 17A - METHYL - 5 - ANDROSTENE 11B,17B- DIACYLATES,3B,11B,17B- TRIHYDROXY-17AMETHYL - 5 - ANDROSTENE 3B,11B,17B -TRIACYLATES, 3B,17B-DIHYDROXY - 17A - METHYL - 5 -ANDROSTEN - 11 - ONE,3B, 17BDIHYDROXY - 17A - METHYL - 5 - ANDROSTEN-11-ONE 3B-ACYLATE, 3B,17B - DIHYDROXY - 17A - METHYL - 5 - ANDROSTEN - 11-ONE 3B, 17B -DIACYLATE,WHERREIN THE ACYL RADICAL IS OF A HYDROCARBON CARBOXYLIC ACIDCONTAINING FROM ONE TO NINE CARBON ATOMS, INCLUSIVE.